Physiology and Pathophysiology

Penile erection is a neurovascular event modulated by psychological factors and hormonal status depending on appropriate trabecular smooth muscle and arterial relaxation in the corpus cavernosum (Fig. 1). On sexual stimulation, nerve impulses cause the release of cholinergic and non-adrenergic non-cholinergic (NANC) neurotransmitters that mediate erectile function by relaxing the smooth muscle of the corpus cavernosum. A principal neural mediator of erection is NO which activates guanil cyclase to form intracellular cyclic guanosine monophosphate (GMP), a potent second messenger for smooth muscle relaxation. Cyclic GMP in turn activates a specific protein kinase, which phosphorylates certain proteins and ion channels, resulting in a drop of cytosolic calcium concentrations and relaxation of the smooth muscle. During the return to the flaccid state, cyclic GMP is hydrolyzed GMP by phosphodiesterase (PDE) type 5. In the corpus cavernosum four PDE isoforms have been

Guanil Cyclase
FIGURE 1 Mechanisms of erection mediated by cavernosal smooth muscle relaxation including the generation of nitric oxide (NO) by nitric oxide synthase (NOS), which is impaired in diabetes.

identified (types 2, 3, 4, and 5), but PDE-5 is the predominant isoform, while the others do not appear to have an important role in erection (109).

The pathogenesis of ED in diabetes is thought to be multifactorial as it may be linked to neuropathy, accelerated atherosclerosis, and alterations in the corporal erectile tissue. Such alterations may include smooth muscle degeneration, abnormal collagen deposition, and endothelial cell dysfunction (110). If irreversible, these corporal degenerative changes can limit the success of any pharmacotherapy. AGEs have been shown to quench NO and to be elevated in human diabetic penile tissue. It has been hypothesized that AGEs may mediate ED via upregulation of inducible nitric oxide synthase and downregulation of endothelial NOS (eNOS) (111). Furthermore, PKC activation by diabetes may reduce NOS activity (112).

In vivo studies of isolated corpus cavernosum tissue from diabetic men have shown functional impairment in neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle (113). In diabetic rats endothelium-dependent NO-mediated relaxation to acetylcholine and NANC stimulation are reduced by 40% after 4 to 8 weeks (114). These alterations were prevented by administration of the anti-oxidant a-lipoic acid, suggesting an involvement of increased oxidative stress. In contrast, endothelium-indepen-dent relaxation to the NO donor sodium nitroprusside is not impaired by diabetes (114). Increased penile endothelial and total NOS activity was found after 2 to 3 months in diabetic rats (115). After 4 to 8 months, however, reduced penile total (endothelial and neuronal) NOS activity and neuronal NOS levels were observed in type 1 and type 2 diabetic rats. (116). Thus, diabetes-induced changes in NOS activity may be biphasic, with an initial increase followed by a decrease. Because RhoA/Rho-kinase may suppress eNOS, RhoA/Rho-kinase could contribute to diabetes-related ED and downregulation of eNOS. Colocalization of Rho-kinase and eNOS protein is present in the endothelium of the corpus cavernosum. Diabetic rats transfected with an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in control rats. AAVT19NRhoA gene transfer improved erectile responses in the diabetic rats to values similar to controls. Thus, activation of the RhoA/Rho-kinase pathway may represent one important mechanism for the downregulation of penile eNOS in diabetes, implying that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity and thereby restores erectile function in diabetes (117).

Diagnosis

A good clinical history and physical examination are the basis of assessment. It is important to establish the nature of the erectile problem and to distinguish it from other forms of sexual difficulty such as penile curvature or premature ejaculation. An interview with the partner is advisable and will confirm the problem but may also reveal other causes of the difficulties, e.g., vaginal dryness. The relative importance of psychological and organic factors may be determined from the history. Drugs which may be associated with ED include tranquillizers (phenothiazines, benzodiazepines), antidepressants (tricyclics, SSRI), and antihypertensives (P-blockers, vasodilators, central sympathomimetics, ganglion blockers, diuretics, ACE inhibitors) (100). In most patients sophisticated investigation is not indicated. A three-step diagnostic approach is shown in Table 9. A detailed history is most important, and for many patients examination can be limited to the regular monitoring of diabetes and its risk factors and complications as well as examination of the genitalia. Patients should be informed about

TABLE 9 Practical Three-step Algorithm for Diagnosis of Erectile Dysfunction Step 1

General sexual history

Clinical examination; relevant laboratory parameters Information about treatment options Step 2

Therapeutic trial with PDE-5 inhibitor Step 3

Intracavernous pharmacotesting: color Doppler or duplex ultrasound of penile arteries the advantages and disadvantages of each treatment and given advice on treatment outcome and ease of use. Even if the cause is organic, almost all men with ED will be affected psychologically. Sexual counseling is an important aspect of any treatment, and it is preferable to also involve the partner.

The second Princeton consensus on sexual dysfunction and cardiac risk issued new guidelines for sexual medicine emphasizing that ED is an early symptom or harbinger of cardiovascular disease, due to the common risk factors and pathophysiology mediated through endothelial dysfunction. Major comorbidities include diabetes, hypertension, hyperlipidemia and heart disease. Any asymptomatic man who presents with ED that does not have an obvious cause (e.g., trauma) should be screened for vascular disease and have blood glucose, lipids, and blood pressure measurements. Ideally, all patients at risk but asymptomatic for coronary disease should undergo an elective exercise electrocardiogram to facilitate risk stratification. Thus, the recognition of ED as a warning sign of silent vascular disease has led to the concept that a man with ED and no cardiac symptoms is a cardiac (or vascular) patient until proven otherwise (118).

Management

Lifestyle Modification. A stepwise therapeutic approach for ED is shown in Table 10. An algorithm for treatment of ED has been suggested by the Second International Consultation on Erectile and Sexual Dysfunctions (Fig. 2) (100). The initial management should advise the patient to reduce or treat possible risk factors such as obesity, hypertension, hyperlipidemia, or smoking and to optimize glycemic control. However, no studies are available to show that improvement in glycemic control will exert a favorable effect on ED. In fact, the VA CSDM Study could not demonstrate an effect of intensive diabetes therapy maintained for 2 years on ED in type 2 diabetic men (119). Healthy lifestyle factors are associated with maintenance of erectile function in men. A controlled study evaluated the effect of weight loss and increased physical activity on erectile and endothelial functions in obese men. Men randomly assigned to the intervention group received detailed advice about how to achieve a loss of 10% or more in their total body weight by reducing caloric intake and increasing their level of physical activity. Men in the control group were given general information about healthy food choices and exercise. After 2 years the mean International Index of Erectile Function (IIEF) score improved in the intervention group from 13.9 to 17points, but not in the control group. In multivariate analyses, changes in body mass index (BMI), physical activity, and C-reactive

TABLE 10 Stepwise Algorithm for Treatment of Erectile Dysfunction

General management Control of risk factors and diabetes; sexual counseling

First-line therapy

Pharmacological treatment Sildenafil (Viagra®), 50-100 mg

Vardenafil (Levitra®), 10-20 mg Tadalafil (Cialis®), 10-20 mg Oral therapy inappropriate Transurethral alprostadil (MUSE), 500-1000 ^g Intracavernosal injection therapy: Alprostadil (Caverject®), 5-20 ^g Papaverine/Phentolamine (Androskat®) Thymoxamine (Erecnos®), 10-20 mg VIP/Phentolamine (Invicorp®) Papaverine/phentolamine/alprostadil (Trimix®)

Surgery and mechanical treatments Pharmacological therapy inappropriate

Vacuum devices Arterial/venous surgery Penile prostheses

Treatment Strategy of Erectile dysfunction (Algorithm)

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